I am a classically trained exercise physiologist, and the research aims of this proposal are to advance knowledge in the field on the link between exercise training and the regulation of hepatic glucose metabolism. Despite the fact that insulin's ability to regulate blood glucose homeostasis is impaired in people with type 2 diabetes mellitus (DM), and despite the well known effect of aerobic exercise training to improve hepatic insulin sensitivity, very little is known about how this improvement relates to the central role of the liver to take up glucose during the postprandial state and produce glucose during the fasted state. Instead, a lion's share of the research on exercise-induced increases in insulin sensitivity have focused on skeletal muscle. Because of the paucity of data in this area, I am proposing to focus my career on studying how aerobic exercise training improves the liver's ability to regulate blood glucose homeostasis in humans with DM. The combination of my clinical research experience as a Ph.D. student and my more recently developed expertise in liver glucose metabolism as a fellow and Instructor in Dr. Cherrington's lab make me uniquely suited to carry out the proposed studies. The broad aim of my experiments is to clarify how physiological outcomes related to hepatic glucose metabolism are improved in response to exercise-induced gains in hepatic insulin sensitivity in humans with DM. Specific aim #1 is to determine how aerobic exercise training, weight loss and their interaction improve splanchnic glucose uptake (SGU) in humans with DM. SGU will be measured using the oral glucose load-clamp method. This important question will be answered by comparing the rates of SGU before and after 12 weeks of exercise without weight loss, weight loss without exercise and aerobic exercise with weight loss, to SGU in non-exercise, non-weight loss controls. Aim #2 is to determine the intrahepatic metabolic pathway(s) that are responsible for the known reductions in hepatic glucose production (HGP) during the basal state and in response to physiological hyperinsulinemia. HGP will be measured using 3-3H glucose during isoglycemic-hyperinsulinemia, while gluconeogenesis and glycogenolysis will be measured using 2H2O. This question will be answered by comparing the rates of HGP, gluconeogenesis and glycogenolysis before and after 12 weeks of aerobic exercise plus weight loss to rates in non-exercise non-weight loss controls. Studies will be performed at Vanderbilt's clinical research center, a premier facility with all of the clinical expertise required to execute these studies in well controlled environment. In addition to the development of my research skills, I am also submitting a career development plan that includes additional coursework related to my future as a translational scientist, a plan to improve my teaching skills, attendance at professional development seminars, a research and career development mentoring committee made up of leaders in the field of diabetes-related research and a concise timeline outlining my career development. When completed, the training I will undergo will equip me with all of the skills necessary to become an independent academic faculty member at Vanderbilt or, if necessary, elsewhere. It is my ultimate goal to become a resourceful faculty member at a major academic institution and a capable leader of my own translational science lab that will serve the scientific community by linking exercise-induced improvements to hepatic insulin sensitivity with improved metabolic function of the liver in people with DM. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus is a metabolic disease that affects the lives of approximately 24 million Americans, and costs the health care system billions of dollars annually. Because of its profound effect on diabetes, aerobic exercise training has become a cornerstone in its treatment, although despite its important role in the regulation of whole body glucose metabolism, very little is known about the effect of exercise on hepatic glucose metabolism. The experiments proposed in this application will lead to a more comprehensive understanding of how exercise training improves liver function in humans with diabetes.